The case of azodicarbonamide ADCA a chemical sensitizer
The case of azodicarbonamide (ADCA) a chemical sensitizer? A. Schnuch, H. Lessmann Göttingen, Germany Chemical Respiratory Allergy, 27 th and 28 th october 2016, Madrid
Background: ADCA is a chemical which is mainly used as a foaming agent in the production of wallpapers, undercoatings for cars, various building materials such as foamed seals and pipe insulation, the coating on table tennis bats, synthetic leather, floor coverings etc Since 1977 reports on respiratory symptoms are suspected to be related to exposure to ADCA From the midst of the 90 ies onwards (almost) no cases Hence the question: Is ADCA really a respiratory sensitizer ? ADCA was identified as a Substance of Very High Concern (SVHC) in 2012 by ECHA considering its hazard classification as a respiratory sensitiser GHS Hazard Statement Code: H 334 – May cause allergy or asthma symptoms or breathing difficulties if inhaled. 2
Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area „MAK – Commission“ The MAK Commission proposes maximum workplace concentrations (MAK values) for volatile chemicals 3
„MAK – Commission“ Substances which are carcinogenic, germ cell mutagenic, sensitising or absorbed percutaneously or which pose a „sa“ (sensitising aiways) „sh“ (sensitising skin) risk during pregnancy are classified accordingly. 4
Human & Experimental Toxicology (2002) 21, 439 444 Criteria for the evaluation of respiratory allergens: Sufficient evidence studies or case reports of a specific hypersensitivity of the airways or the lungs - indicative of an immunological mechanism from more than one patient and at least two independent centres. the symptoms…. must be shown to be associated with the exposure to the substance. 5
Substances characterized by “sufficient evidence” are generally designated as allergens with “Sa” substances are not designated with an ”Sa" if in spite of extensive handling of the substance, very few cases of sensitisation are observed 6
The case of azodicarbonamide (ADCA) a chemical sensitizer? Data: 1. Well documented reports on 3 cases from 2 centers. 2. Less well or poorly documented reports on several cases from three centers. 3. “Epidemiological” studies on exposure measurements and on workers with respiratory symptoms from three plants. 4. Notification of suspected, yet not diagnosed cases to registers of occupational health (e. g. SWORD). 7
Case reports with documented diagnostic literature / cases Exposure/ latency provocation method prov. time late reaction ? max. fall of FEV 1 unspecific bronch. Hyperr hyperreactivity after provoc. ↑ ? neg. controls prick- /patchtest other symptoms industry / job / co-exposure Malo et al. 1985 / 1 (a) 1 (b) „few months“ (3 4 times per y / 1 2 („irregular exposure“) weeks exposure) „from 1 tray to another“ / exposure chamber / lactose ADCA mixture 1: 1 Kim et al. 2004 / 1 7 years „fr 1 tr to an“ / 30 g (? ) lactose ADCA mixture 1: 1 15 sec 10 min yes dual (yes) (continous reaction with max. after 5 h) 24% 26% and 23% 22% yes (2 mg/ml 0, 28) no (0, 5 1, 2) n. s. Yes (4. 7 0, 47) n. d. Rhinitis (non atopic) plastics ind. / ? yes (2) neg. / pos. preparation of ADCA / quality control / (? ) yes (1) n. d. eye irritation /atopic plastics ind. / ? 8
Case reports with less well documented diagnostic literature / cases Exposure/ latency provocation method prov. time late reaction ? Normand et al. 1989 / 1 (a) 1 year ? Normand et al. 1989 / 1 (b) 2 months ? ? Normand et al. 1989 / 2 (c+d) no ? (exposure 2 weeks per year) n. d. 40 min n. d. no (but patient (yes) (continous reported reaction with max. at night 14 h later) after 3 4 h) n. rep. max. fall of FEV 1 ( < 7%) 22% n. d. industry / job / co-exposure plastics ind. / mixing/milling of pigments and blowing agents / > 30 substances; also diisocyanates ? plastics ind. / mixing/milling of pigments and blowing agents / > 30 subst. (? ) plastics ind. / ? Valentino 1985 / 1 Ferris et al. 1977 / 6 -9 (? ) 1 year „shortly“ (n. m. d. ) (a) moving glas workplace related plate (100 g) „provocation“ (b)workplace (0. 7 to 2. 1 mg/m 3) „provocation“ (a) 60 min and working shift (b) during shift (a) no / (b) yes decrease of mean (continuous; max FEV 1 in total group over 4 h after end of shift (? ) measured on 3 shift) days neg. / up to 50% FVC Ø about 17%, 5%, 6% FEV 1 Ø about 21%, 8%, 10% plastics ind. / milling of ADCA / injection molding / confectionning / Polyurethanes „herbicide“, sulfanilamide, Al 2 O 3, Si. O 2 … Improvement 9 after DSCG
Respiratory sensitisation “Epidemiological” studies SLOVAK 1981 Thorax 36: 906 -909 (1981) All 151 personnel …who had been or were currently engaged in manufacture, servicing and quality control on the AC plant since its opening in 1966 were included Past Twenty eight (18. 5 %) people without previous asthma gave a history of episodes of late onset asthma after exposure to azodicarbonamide. Seven of 13 sensitised individuals who were still exposed three months after the onset of disease developed prolonged airways hyperreactivity to common environmental irritants. Levels of exposure not determined Spirometry not done 10
Respiratory sensitisation “Epidemiological” studies SLOVAK 1981 (Despite ) „quite high” average levels in the range 2 -5 mg/m 3. Presence No symptoms; no difference between holidays and work Pre and post shift spirometry: No change . . . ? 11
Respiratory sensitisation “Epidemiological” studies NIOSH / Ahrenholz et al. 1985: Armstrong World Industries Floor Plant, Lancaster, Pennsylvania. occurrence of nose bleeds, skin rashes, and mucous membrane irritation among workers handling powdered azodicarbonamide. Exposure in 2 buildings: (mean) 3. 8 mg / m 3 and 1. 6 mg / m 3 with use of personal protection at high exposures 18/30 (60%) exposed workers with resp. symptoms / 8 suspected to be ADCA related Pre and post shift pulmonary functions tests (mean FVC and FEV 1) did not differ between exposed and not exposed; no specific Ig. E detected 12
Respiratory sensitisation “Epidemiological” studies NIOSH / Ahrenholz and Anderson 1985: Dep. Env. Ind Health / Univ. Michigan / LW Whitehead et al 1987 health hazard evaluation and systematic study of respiratory health variables at Leon Plastics in Grand Rapids, Michigan. of particular concern: the injection molding department 223 (out of 242 employees) were studied. Pulmonary functions (mean FEV 1 and FVC) did not differ between formerly exposed (n=60), currently exposed (n=110) and never exposed (n= 57) However, strong association with eye/nose/throat irritation, cough and wheezing and symptoms of chronic bronchitis in exposed workers 13
Respiratory sensitisation “Epidemiological” studies Dep. Env. Ind Health / Univ. Michigan / LW Whitehead et al 1987 These results suggest respiratory symptom causation by some combination of azodicarbonamide itself, reaction products of azodicarbonamide formed during injection molding, or other unidentified agents. 14
Respiratory sensitisation Registration systems Surveillance of Work-Related and Occupational Respiratory Disease (SWORD, GB) …. . provide no clues as to the question of sensitisation 15
Respiratory sensitisation ? Human experiences, summary • At most 3 conclusive cases in which pulmonary reactions have been verified in sufficiently documented provocation tests (1 x Korea, 2 x Canada) • In spite of some shortcomings, these 2 case reports give some evidence for an immunological mechanism and could therefore be regarded as sufficient to fullfill the criteria for marking ADCA with „Sa“ • Further case reports are inconclusive and/or insufficiently documented • No allergological diagnostics have been done in epidemiological studies from the workplace and no such information is available for cases from registration systems 16
Exposure / Causality Additives From the Encyclopaedia Britannica 2016: • azodicarbonamide, usually compounded with some other ingredients in order to modify the decomposition temperature and to aid in dispersion of the agent in the resin. . 17
Exposure / Causality Additives e. g. dicarbonic acid anhydrides as „desiccants“ 18
„chemical embossing“ 2011 19
Respiratory sensitisation ? Exposure / Causality • The identity/purity of the ADCA as used in provocation tests is not documented in any case report! • Hence, the real aetiopathogenic exposure is not definitely known • The fine dust particles, possibly in combination with other factors (especially in the plastics industry) may also be causative • Causality of decomposition products has not been evaluated in the plastics industry • Further exposure scenarios may be involved, regarding information from some patent literature 20
Activity of ADCA An alternative view • ADCA (an electrophil) would preferentially react with weak and easily polarisable nucleophiles like thiols (=SH), and less (if at all) with aminogroups (=NH 2) Sequelae: • ADCA would act as an oxidant, e. g. in oxidizing Glutathion (GSH) to GS SG, Danger signals, Intracellular thereby reducing the antioxidant capacities signalling – Inflammation • Resulting finally in a state of „oxidative stress“ 21
ADCA as oxidant for SH groups GS SG GSH 22
ADCA closely resembles „diamide“ Intrinsic reactivities of ADCA and diamide are very probably closely related. Diamide was used in a multitude of in vitro studies as selective „thiol-probe“ or as inducer of „oxidative stress“ 23
ADCA – a respiratory sensitiser ? Overall Summary 1. Findings from only 3 cases from 2 centres may be interpreted as being caused by immunological mechanisms (→ „allergen“). 2. Regarding the (former) relatively wide distribution/exposure, these rare cases provide only little evidence for a relevant sensitising potential 3. An assumed sensitising effect is contradicted by the negative result in the LLNA and other predictive tests, which is in contrast to almost all known low molecular weight respiratory allergens 4. There are (possibly) several alternative causes due to a highly suspected co exposure 5. It is of utmost importance to recognize that the identity of the causal exposure is not clear cut documented A respiratory sensitising effect of azodicarbonamide is not sufficiently proven. ADCA is not designated with „Sa“ 24
Thank you for your attention 25
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